4,5-disubstituted imidazole compounds

ABSTRACT

The present invention is directed to novel 4,5-disubstituted imidazole compounds, and compositions for use in therapy as an anti-inflammatory agent, and as an inhibitor of cytokine p38/MAP kinase mediated diseases.

RELATED APPLICATIONS

This application is the §371 national stage entry of PCT/US97/14731,filed Aug. 21, 1996 which claims the benefit of provisional applicationsNo. 60/024,753, filed Aug. 21, 1996 and No. 60/050,223, filed Jun. 19,1997.

FIELD OF THE INVENTION

This invention relates to a novel group of imidazole containingcompounds, processes for the preparation thereof, the use thereof intreating cytokine mediated diseases and pharmaceutical compositions foruse in such therapy.

BACKGROUND OF THE INVENTION

Interleukin-1 (IL-1) and Tumor Necrosis Factor (TNF) are biologicalsubstances produced by a variety of cells, such as monocytes ormacrophages. IL-1 has been demonstrated to mediate a variety ofbiological activities thought to be important in immunoregulation andother physiological conditions such as inflammation [See, e.g.,Dinarello et al., Rev. Infect. Disease, 6, 51 (1984)]. The myriad ofknown biological activities of IL-1 include the activation of T helpercells, induction of fever, stimulation of prostaglandin or collagenaseproduction, neutrophil chemotaxis, induction of acute phase proteins andthe suppression of plasma iron levels.

There are many disease states in which excessive or unregulated IL-1production is implicated in exacerbating and/or causing the disease.These include rheumatoid arthritis, osteoarthritis, endotoxemia and/ortoxic shock syndrome, other acute or chronic inflammatory disease statessuch as the inflammatory reaction induced by endotoxin or inflammatorybowel disease; tuberculosis, atherosclerosis, muscle degeneration,cachexia, psoriatic arthritis, Reiter's syndrome, rheumatoid arthritis,gout, traumatic arthritis, rubella arthritis, and acute synovitis.Recent evidence also links IL-1 activity to diabetes and pancreatic βcells.

Dinarello, J. Clinical Immunology, 5 (5), 287-297 (1985), reviews thebiological activities which have been attributed to IL-1. It should benoted that some of these effects have been described by others asindirect effects of IL-1.

Excessive or unregulated TNF production has been implicated in mediatingor exacerbating a number of diseases including rheumatoid arthritis,rheumatoid spondylitis, osteoarthritis, gouty arthritis and otherarthritic conditions; sepsis, septic shock, endotoxic shock, gramnegative sepsis, toxic shock syndrome, adult respiratory distresssyndrome, cerebral malaria, chronic pulmonary inflammatory disease,silicosis, pulmonary sarcoisosis, bone resorption diseases, reperfusioninjury, graft vs. host reaction, allograft rejections, fever andmyalgias due to infection, such as influenza, cachexia secondary toinfection or malignancy, cachexia, secondary to acquired immunedeficiency syndrome (AIDS), AIDS, ARC (AIDS related complex), keloidformation, scar tissue formation, Crohn's disease, ulcerative colitis,or pyresis.

AIDS results from the infection of T lymphocytes with HumanImmunodeficiency Virus (HIV). At least three types or strains of HIVhave been identified, i.e., HIV-1, HIV-2 and HIV-3. As a consequence ofHIV infection, T-cell mediated immunity is impaired and infectedindividuals manifest severe opportunistic infections and/or unusualneoplasms. HIV entry into the T lymphocyte requires T lymphocyteactivation. Other viruses, such as HIV-1, HIV-2 infect T lymphocytesafter T Cell activation and such virus protein expression and/orreplication is mediated or maintained by such T cell activation. Once anactivated T lymphocyte is infected with HIV, the T lymphocyte mustcontinue to be maintained in an activated state to permit HIV geneexpression and/or HIV replication. Monokines, specifically TNF, areimplicated in activated T-cell mediated HIV protein expression and/orvirus replication by playing a role in maintaining T lymphocyteactivation. Therefore, interference with monokine activity such as byinhibition of monokine production, notably TNF, in an HIV-infectedindividual aids in limiting the maintenance of T cell activation,thereby reducing the progression of HIV infectivity to previouslyuninfected cells which results in a slowing or elimination of theprogression of immune dysfunction caused by HIV infection. Monocytes,macrophages, and related cells, such as kupffer and glial cells, havealso been implicated in maintenance of the HIV infection. These cells,like T-cells, are targets for viral replication and the level of viralreplication is dependent upon the activation state of the cells. [SeeRosenberg et al., The Immunopathogenesis of HIV Infection, Advances inImmunology, Vol. 57, (1989)]. Monokines, such as TNF, have been shown toactivate HIV replication in monocytes and/or macrophages [See Poli, etal., Proc. Natl. Acad. Sci., 87:782-784 (1990)], therefore, inhibitionof monokine production or activity aids in limiting HIV progression asstated above for T-cells.

TNF has also been implicated in various roles with other viralinfections, such as the cytomegalia virus (CMV), influenza virus, andthe herpes virus for similar reasons as those noted.

Interleukin-8 (IL-8) is a chemotactic factor first identified andcharacterized in 1987. IL-8 is produced by several cell types includingmononuclear cells, fibroblasts, endothelial cells, and keratinocytes.Its production from endothelial cells is induced by IL-1, TNF, orlipopolysachharide (LPS). Human IL-8 has been shown to act on Mouse,Guinea Pig, Rat, and Rabbit Neutrophils. Many different names have beenapplied to IL-8, such as neutrophil attractant/activation protein-1(NAP-1), monocyte derived neutrophil chemotactic factor (MDNCF),neutrophil activating factor (NAF), and T-cell lymphocyte chemotacticfactor.

IL-8 stimulates a number of functions in vitro. It has been shown tohave chemoattractant properties for neutrophils, T-lymphocytes, andbasophils. In addition it induces histamine release from basophils fromboth normal and atopic individuals as well as lysozomal enzyme releaseand respiratory burst from neutrophils. IL-8 has also been shown toincrease the surface expression of Mac-1 (CD11b/CD18) on neutrophilswithout de novo protein synthesis, this may contribute to increasedadhesion of the neutrophils to vascular endothelial cells. Many diseasesare characterized by massive neutrophil infiltration. Conditionsassociated with an increased in IL-8 production (which is responsiblefor chemotaxis of neutrophil into the inflammatory site) would benefitby compounds which are suppressive of IL-8 production.

IL-1 and TNF affect a wide variety of cells and tissues and thesecytokines as well as other leukocyte derived cytokines are important andcritical inflammatory mediators of a wide variety of disease states andconditions. The inhibition of these cytokines is of benefit incontrolling, reducing and alleviating many of these disease states.

There remains a need for treatment, in this field, for compounds whichare cytokine suppressive anti-inflammatory drugs, i.e. compounds whichare capable of inhibiting cytokines, such as IL-1, IL-6, IL-8 and TNF.

SUMMARY OF THE INVENTION

This invention relates to the novel compounds of Formula (I) andpharmaceutical compositions comprising a compound of Formula (I) and apharmaceutically acceptable diluent or carrier.

This invention also relates to a method of inhibiting cytokines and thetreatment of a cytokine mediated disease, in a mammal in need thereof,which comprises administering to said mammal an effective amount of acompound of Formula (I).

In particular the present invention relates to a method of treating aCSBP/RK/p38 kinase mediated disease, in a mammal in need thereof.

This invention more specifically relates to a method of inhibiting theproduction of IL-1 in a mammal in need thereof which comprisesadministering to said mammal an effective amount of a compound ofFormula (I).

This invention more specifically relates to a method of inhibiting theproduction of IL-8 in a mammal in need thereof which comprisesadministering to said mammal an effective amount of a compound ofFormula (I).

This invention more specifically relates to a method of inhibiting theproduction of TNF in a mammal in need thereof which comprisesadministering to said mammal an effective amount of a compound ofFormula (I).

Accordingly, the present invention provides for a compound of thestructure:

wherein:

R₁ is 4-pyridyl, pyrimidinyl, 4-pyridazinyl, 1,2,4-triazin-5-yl,quinolyl, isoquinolinyl, quinazolin-4-yl, 1-imidazolyl or1-benzimidazolyl, which heteroaryl ring is optionally substitutedindependently one to three times with Y, NHR_(a), optionally substitutedC₁₋₄ alkyl, halogen, hydroxyl, optionally substituted C₁₋₄ alkoxy,optionally substituted C₁₋₄ alkylthio, C₁₋₄ alkylsulfinyl, CH₂OR₁₂,amino, mono and di-C₁₋₆ alkyl substituted amino, N(R₁₀)C(O)R_(b), or anN-heterocyclyl ring which ring has from 5 to 7 members and optionallycontains an additional heteroatom selected from oxygen, sulfur;

Y is X₁—R_(a);

X₁ is oxygen or sulfur;

R₄ is phenyl, naphth-1-yl or naphth-2-yl, or a heteroaryl, which isoptionally substituted by one or two substituents, each of which isindependently selected, and which, for a 4-phenyl, 4-naphth-1-yl,5-naphth-2-yl or 6-naphth-2-yl substituent, is halogen, cyano, nitro,C(Z)NR₇R₁₇, C(Z)OR₁₆, (CR₁₀R₂₀)_(v)COR₁₂, SR₅, SOR₅, OR₁₂,halo-substituted-C₁₋₄ alkyl, C₁₋₄ alkyl, ZC(Z)R₁₂, NR₁₀C(Z)R₁₆, or(CR₁₀R₂₀)_(v)NR₁₀R₂₀ and which, for other positions of substitution, ishalogen, cyano, C(Z)NR₁₃R₁₄, C(Z)OR₃, (CR₁₀R₂₀)_(m″)COR₃, S(O)_(m)R₃,OR₃, halo-substituted-C₁₋₄ alkyl, C₁₋₄ alkyl, (CR₁₀R₂₀)_(m″)NR₁₀C(Z)R₃,NR₁₀S(O)_(m′)R₈, NR₁₀S(O)_(m′)NR₇R₁₇, ZC(Z)R₃ or (CR₁₀R₂₀)_(m″)NR₁₃R₁₄;

v is 0, or an integer having a value of 1 or 2;

m is 0, or the integer 1 or 2;

m′ is an integer having a value of 1 or 2,

m″ is 0, or an integer having a value of 1 to 5;

n is an integer having a value of 1 to 10;

n′ is 0, or an integer having a value of 1 to 10;

Z is oxygen or sulfur;

R_(a) is C₁₋₆alkyl, aryl, arylC₁₋₆alkyl, heterocyclic, heterocyclylC₁₋₆alkyl, heteroaryl, heteroarylC₁₋₆alkyl, wherein each of these moietiesmay be optionally substituted;

R_(b) is hydrogen, C₁₋₆alkyl, C₃₋₇ cycloalkyl, aryl, arylC₁₋₄ alkyl,heteroaryl, heteroarylC₁₋₄alkyl, heterocyclyl, or heterocyclylC₁₋₄alkyl;

R₃ is heterocyclyl, heterocyclylC₁₋₁₀ alkyl or R₈;

R₅ is hydrogen, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl or NR₇R₁₇,excluding the moieties —SR₅ being —SNR₇R₁₇ and —SOR₅ being —SOH;

R₇ and R₁₇ is each independently selected from hydrogen or C₁₋₄ alkyl orR₇ and R₁₇ together with the nitrogen to which they are attached form aheterocyclic ring of 5 to 7 members which ring optionally contains anadditional heteroatom selected from oxygen, sulfur or NR₁₅;

R₈ is C₁₋₁₀ alkyl, halo-substituted C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₃₋₇ cycloalkyl, C₅₋₇ cycloalkenyl, aryl, arylC₁₋₁₀ alkyl,heteroaryl, heteroarylC₁₋₁₀ alkyl, (CR₁₀R₂₀)_(n)OR₁₁,(CR₁₀R₂₀)_(n)S(O)_(m)R₁₈, (CR₁₀R₂₀)_(n)NHS(O)₂R₁₈, (CR₁₀R₂₀)_(n)NR₁₃R₁₄;wherein the aryl, arylalkyl, heteroaryl, heteroaryl alkyl may beoptionally substituted;

R₉ is hydrogen, —C(Z)R₁₁ or optionally substituted C₁₋₁₀ alkyl,S(O)₂R₁₈, optionally substituted aryl or optionally substitutedaryl-C₁₋₄ alkyl;

R₁₀ and R₂₀ is each independently selected from hydrogen or C₁₋₄ alkyl;

R₁₁ is hydrogen, C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, heterocyclyl,heterocyclyl C₁₋₁₀alkyl, aryl, arylC₁₋₁₀ alkyl, heteroaryl orheteroarylC₁₋₁₀ alkyl;

R₁₂ is hydrogen or R_(l6);

R₁₃ and R₁₄ is each independently selected from hydrogen or optionallysubstituted C₁₋₄ alkyl, optionally substituted aryl or optionallysubstituted aryl-C₁₋₄ alkyl, or together with the nitrogen to which theyare attached form a heterocyclic ring of 5 to 7 members which ringoptionally contains an additional heteroatom selected from oxygen,sulfur or NR₉;

R₁₅ is R₁₀ or C(Z)—C₁₋₄ alkyl;

R₁₆ is C₁₋₄ alkyl, halo-substituted-C₁₋₄ alkyl, or C₃₋₇ cycloalkyl;

R₁₈ is C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, heterocyclyl, aryl, arylalkyl,heterocyclyl, heterocyclyl-C₁₋₁₀ alkyl, heteroaryl or heteroarylalkyl;

or a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

In Formula (I), suitable R₁ moieties includes 4-pyridyl, 4-pyrimidinyl,4-pyridazinyl, 1,2,4-triazin-5-yl, 4-quinolyl, 6-isoquinolinyl,4-quinazolinyl, 1-imidazolyl and 1-benzimidazolyl rings, of which the4-pyridyl, 4-pyrimidinyl and 4-quinolyl rings are preferred. Morepreferred is the 4-pyrimidinyl or 4-pyridyl moiety, and most preferredis the 4-pyrimidinyl ring.

Suitably, the R₁ ring is optionally substituted independently one tothree times with Y, NHR_(a), optionally substituted C₁₋₄ alkyl, halogen,hydroxyl, optionally substituted C₁₋₄ alkoxy, optionally substitutedC₁₋₄ alkylthio, C₁₋₄ alkylsulfinyl, CH₂OR₁₂, amino, mono and di-C₁₋₆alkyl substituted amino, N(R₁₀)C(O)R_(b), or an N-heterocyclyl ringwhich ring has from 5 to 7 members and optionally contains an additionalheteroatom selected from oxygen, sulfur.

Suitably, Y is X₁—R_(a); and X₁ is oxygen or sulfur, preferably oxygen.

Suitably, R_(a) is C₁₋₆alkyl, aryl, arylC₁₋₆alkyl, heterocyclic,heterocyclicC₁₋₆ alkyl, heteroaryl, or heteroarylC₁₋₆alkyl; and whereineach of these moieties may be optionally substituted. Preferably R_(a)is an optionally substituted C₁₋₆alkyl, aryl, or aryl C₁₋₆alkyl group.

When R_(a) is an aryl, it is preferably phenyl or napthyl. When R_(a) isarylalkyl, it it is preferably benzyl or napthylmethyl. When R_(a) is aheterocyclic or heterocyclic alkyl moiety, the heterocyclic portion ispreferably pyrrolindinyl, piperidine, morpholino, tetrahydropyran,tetrahydrothiopyranyl, tetrahydrothipyransulfinyl,tetrahydrothio-pyransulfonyl, pyrrolindinyl, indole, or piperonyl ring.It is noted that the heterocyclic rings herein may contain unsaturation,such as in a tryptamine ring.

When R_(a) is a heteroaryl ring as defined below, it is preferably apyridine or tetrazole ring.

The R_(a) moieties may be optionally substituted one or more times,preferably one to three times, independently with halogen; C₁₋₄ alkyl,such as methyl, ethyl, propyl, isopropyl, or t-butyl; halosubstitutedalkyl, such as CF₃; hydroxy; hydroxy substituted C₁₋₄ alkyl; (CR₁₀R₂₀)qC₁₋₄ alkoxy, such as methoxy or ethoxy; CR₁₀R₂₀)q S(O)_(m)alkyl and;(CR₁₀R₂₀)qS(O)_(m) aryl (wherein m is 0, 1, or 2); (CR₁₀R₂₀)qC(O)OR₁₁,such as C(O)C₁₋₄ alkyl or C(O)OH moieties; (CR₁₀R₂₀)qC(O)R₁₁;(CR₁₀R₂₀)qOC(O)R_(c); —O—(CH₂)s-O—, such as in a ketal or dioxyalkylenebridge; (CR₁₀R₂₀)qNR₁₃R₁₄; (CR₁₀R₂₀)qN(R₁₀)C(O)R_(b);(CR₁₀R₂₀)qC(O)NR₁₃R₁₄; (CR₁₀R₂₀)qC(O)NR₁₀R_(c); (CR₁₀R₂₀)qS(O)₂NR₁₃R₁₄;(CR₁₀R₂₀)qS(O)₂ NR₁₀R_(c); (CR₁₀R₂₀)qN(R₁₀)S(O)₂ R_(c); cyano, nitro, oran N-heterocyclyl ring which ring has from 5 to 7 members and optionallycontains an additional heteroatom selected from oxygen, sulfur or NR₁₅;aryl, such as phenyl; an optionally substituted arylalkyl, such asbenzyl or phenethyl; aryloxy, such as phenoxy; or arylalkyloxy such asbenzyloxy; and wherein the aryl, alkylaklyl, aryloxy and arylalkyloxymoieties may be optionally substituted themselves one to two times byhalogen; hydroxy; hydroxy substituted alkyl; C₁₋₁₀ alkoxy; S(O)_(m)alkyl; amino, NR₇R₁₇ group; C₁₋₄ alkyl, or halosubstituted C₁₋₄ alkyl.

q is 0 or an integer having a value of 1 to 4.

R_(b) is suitably hydrogen, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, aryl, arylC₁₋₄alkyl, heteroaryl, heteroarylC₁₋₄alkyl, heterocyclyl, orheterocyclylC₁₋₄ alkyl moiety; all of which may be optionallysubstituted as defined below.

R_(c) is suitably an C₁₋₆ alkyl, C₃₋₇ cycloalkyl, aryl, arylC₁₋₄ alkyl,heteroaryl, heteroarylC₁₋₄ alkyl, heterocyclyl, or heterocyclylC₁₋₄alkyl moiety, all of which may be optionally substituted as definedbelow.

Suitable R_(a) groups include,but are not limited to, methyl, ethyl,isopropyl, benzyl, halosubstituted benzyl, napthylmethyl, phenyl,halosubstituted phenyl, aminocarbonylphenyl, alkylphenyl, cyanophenyl,alkylthiophenyl, hydroxyphenyl, alkoxyphenyl, phenoxyphenyl,benzyloxyphenyl, phenylphenyl, methylenedioxyphenyl,trifluoromethylphenyl, methylsulfonylphenyl, tetrazole,methyltetrazolyl, morpholinopropyl, piperonyl, piperidin-4-yl, alkylsubstituted piperidine, such as 1-methyl piperidine, or2,2,6,6-tetramethylpiperidin-4-yl.

When the R₁ optional substituent is N(R₁₀)C(O) R_(b), R_(b) ispreferably a C₁₋₆ alkyl and R₁₀ is preferably hydrogen. It is alsorecognized that the R_(b) moieties, in particular the C₁₋₆ alkyl groupmay be optionally substituted, preferably from one to three times,preferably with halogen, such as fluorine, as in trifluoromethyl ortrifluroethyl.

Preferably R₁ is substituted by Y, such as alkoxy, aryloxy, orarylalkyloxy, NHRa, or amino. A preferred ring placement of the R₁substituent on the 4-pyridyl derivative is the 2-position, such as2-methoxy-4-pyridyl. A preferred ring placement on the 4-pyrimidinylring is also at the 2-position, such as in 2-methoxypyrimidinyl.

Preferably, when the substituent is an optionally substituted C₁₋₄alkyl. The alkyl moiety is preferably substituted by halogen, such asfluorine, chlorine, bromine or iodine; hydroxy, such as hydroxyethoxy;C₁₋₁₀ alkoxy, such as a methoxymethoxy, S(O)m alkyl, wherein m is 0, 1or 2; amino, mono & di-substituted amino, such as in the NR₇R₁₇ group,i.e. tert-butylaminoethoxy; or where the R₇R₁₇ may together with thenitrogen to which they are attached cyclize to form a 5 to 7 memberedring which optionally includes an additional heteroatom selected fromON/S; C₁₋₁₀ alkyl, cycloalkyl, or cycloalkyl alkyl group, such asmethyl, ethyl, propyl, isopropyl, t-butyl, etc. or cyclopropyl methyl;or halosubstituted C₁₋₁₀ alkyl, such as CF₃. Preferably the R₁substituents are tertbutylaminoethoxy, or hydroxyethoxy.

Suitably, R₄ is phenyl, naphth-1-yl or naphth-2-yl, or a heteroaryl,which is optionally substituted by one or two substituents. Morepreferably R₄ is a phenyl or naphthyl ring. Suitable substitutions forR₄ when this is a 4-phenyl, 4-naphth-1-yl, 5-naphth-2-yl or6-naphth-2-yl moiety are one or two substituents each of which areindependently selected from halogen, SR₅, SOR₅, OR₁₂, CF₃, or(CR₁₀R₂₀)_(v)NR₁₀R₂₀, and for other positions of substitution on theserings preferred substitution is halogen, S(O)_(m)R₃, OR₃, CF₃,(CR₁₀R₂₀)_(m″)NR₁₃R₁₄, NR₁₀C(Z)R₃ and NR₁₀S(O)_(m′)R₈. Preferredsubstituents for the 4-position in phenyl and naphth-1-yl and on the5-position in naphth-2-yl include halogen, especially fluoro and chloroand —SR₅ and —SOR₅ wherein R₅ is preferably a C₁₋₂ alkyl, morepreferably methyl; of which the fluoro and chloro is more preferred, andmost especially preferred is fluoro. Preferred substituents for the3-position in phenyl and naphth-1-yl rings include: halogen, especiallyfluoro and chloro; OR₃, especially C₁₋₄ alkoxy; CF₃, NR₁₀R₂₀, such asamino; —NR₁₀C(Z)R₃, especially NHCO(C₁₋₁₀ alkyl); NR₁₀S(O)_(m′)R₈,especially NHSO₂(C₁₋₁₀ alkyl), and SR₃ and —SOR₃ wherein R₃ ispreferably a C₁₋₂ alkyl, more preferably methyl. When the phenyl ring isdisubstituted preferably it is two independent halogen moieties, such asfluoro and chloro, preferably di-chloro and more preferably in the3,4-position. It is also preferred that for the 3-position of both theOR₃ and ZC(Z)R₃ moietites, R₃ may also include hydrogen.

Preferably, the R₄ moiety is an unsubstituted or substituted phenylmoiety. More preferably, R₄ is phenyl or phenyl substituted at the4-position with fluoro and/or substituted at the 3-position with fluoro,chloro, C₁₋₄ alkoxy, methane-sulfonamido or acetamido, or R₄ is a phenyldi-substituted at the 3,4-position independently with chloro or fluoro,more preferably chloro. Most preferably, R₄ is a 4-fluorophenyl.

Suitably, R₄ is an optionally substituted phenyl. Preferably the phenylis substituted one or more times independently by halogen, —SR₅—S(O)R₅,—OR₁₂, halo-substituted-C₁₋₄ alkyl, or C₁₋₄ alkyl.

As used herein, “optionally substituted” unless specifically definedherein, shall mean such groups as halogen, such as fluorine, chlorine,bromine or iodine; hydroxy; hydroxy substituted C₁₋₁₀ alkyl; C₁₋₁₀alkoxy, such as methoxy or ethoxy; S(O)m alkyl, wherein m is 0, 1 or 2,such as methyl thio, methylsulfinyl or methyl sulfonyl; amino, mono &di-substituted amino, such as in the NR₇R₁₇ group; or where the R₇R₁₇may together with the nitrogen to which they are attached cyclize toform a 5 to 7 membered ring which optionally includes an additionalheteroatom selected from O/N/S; C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, or C₃₋₇cycloalkyl alkyl group, such as methyl, ethyl, propyl, isopropyl,t-butyl, etc. or cyclopropyl methyl; halosubstituted C₁₋₁₀ alkyl, suchCF₃; an optionally substituted aryl, such as phenyl, or an optionallysubstituted arylalkyl, such as benzyl or phenethyl, wherein these arylmoieties may also be substituted one to two times by halogen; hydroxy;hydroxy substituted alkyl; C₁₋₁₀ alkoxy; S(O)_(m) alkyl; amino, mono &di-substituted amino, such as in the NR₇R₁₇ group; alkyl, or CF₃.

Suitable pharmaceutically acceptable salts are well known to thoseskilled in the art and include basic salts of inorganic and organicacids, such as hydrochloric acid, hydrobromic acid, sulphuric acid,phosphoric acid, methane sulphonic acid, ethane sulphonic acid, aceticacid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid,succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid,phenylacetic acid and mandelic acid. In addition, pharmaceuticallyacceptable salts of compounds of Formula (I) may also be formed with apharmaceutically acceptable cation, for instance, if a substituent groupcomprises a carboxy moiety. Suitable pharmaceutically acceptable cationsare well known to those skilled in the art and include alkaline,alkaline earth, ammonium and quaternary ammonium cations.

The following terms, as used herein, refer to:

“halo” or “halogens”, include the halogens: chloro, fluoro, bromo andiodo.

“C₁₋₁₀alkyl” or “alkyl”—both straight and branched chain radicals of 1to 10 carbon atoms, unless the chain length is otherwise limited,including, but not limited to, methyl, ethyl, n-propyl, iso-propyl,n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl and the like.

“aryl”—phenyl and naphthyl.

“cycloalkyl” is used herein to mean cyclic radicals, preferably of 3 to8 carbons, including but not limited to cyclopropyl, cyclopentyl,cyclohexyl, and the like.

“heteroaryl” (on its own or in any combination, such as “heteroaryloxy”,or “heteroaryl alkyl”)—a 5-10 membered aromatic ring system in which oneor more rings contain one or more heteroatoms selected from the groupconsisting of N, O or S, such as, but not limited, to pyrrole, pyrazole,furan, thiophene, quinoline, isoquinoline, quinazolinyl, pyridine,pyrimidine, oxazole, thiazole, thiadiazole, triazole, imidazole, orbenzimidazole.

“heterocyclic” (on its own or in any combination, such as“heterocyclylalkyl”)—a saturated or partially unsaturated 4-10 memberedring system in which one or more rings contain one or more heteroatomsselected from the group consisting of N, O, or S; such as, but notlimited to, pyrrolidine, piperidine, piperazine, morpholine, tetrahydropyran, or imidazolidine.

The term “aralkyl” or “heteroarylalkyl” or “heterocyclicalkyl” is usedherein to mean C₁₋₄ alkyl as defined above attached to an aryl,heteroaryl or heterocyclic moiety as also defined herein unlessotherwise indicate.

“sulfinyl”—the oxide S(O) of the corresponding sulfide, the term “thio”refers to the sulfide, and the term “sulfonyl” refers to the fullyoxidized S (O)₂ moiety.

For the purposes herein the “core” 4-pyrimidinyl moiety for R₁ isreferred to as the formula:

Exemplified compounds of Formula (I) include:

4-(4-Fluorophenyl)-5-(4-pyridyl)imidazole

4-(4-Fluorophenyl)-5-(2-methoxy-pyrimidin-4-yl)imidazole

4-(4-Fluorophenyl)-5-(2-methylthio-pyrimidin-4-yl)imidazole

The compounds of Formula (I) may be obtained by applying syntheticprocedures as described in U.S. Ser. No. 08/091,491, published as Adamset al. WO95/02575; U.S. Pat. No. 5,593,992 Adams et al.; and U.S. Ser.No. 08/659,102 published as PCT US96/40143 now U.S. Pat. No. 5,871,834.Synthetic chemistry for each of the variously substituted R₁ moieties iscontained within each noted patent application. A description of theassay for inhibition of the cytokine specific binding protein (CSBP) isalso found in WO95/07922, now U.S. Pat. No. 5,871,934. Each of thesereferences is incorporated herein in their entirety.

Pharmaceutically acid addition salts of compounds of Formula (I) may beobtained in known manner, for example by treatment thereof with anappropriate amount of acid in the presence of a suitable solvent.

Methods of Treatment

The compounds of Formula (I), or a pharmaceutically acceptable saltthereof can be used in the manufacture of a medicament for theprophylactic or therapeutic treatment of any disease state in a human,or other mammal, which is exacerbated or caused by excessive orunregulated cytokine production by such mammal's cell, such as but notlimited to monocytes and/or macrophages.

Compounds of Formula (I) are capable of inhibiting proinflammatorycytokines, such as IL-1, IL-6, IL-8 and TNF and are therefore of use intherapy. IL-1, IL-6, IL-8 and TNF affect a wide variety of cells andtissues and these cytokines, as well as other leukocyte-derivedcytokines, are important and critical inflammatory mediators of a widevariety of disease states and conditions. The inhibition of thesepro-inflammatory cytokines is of benefit in controlling, reducing andalleviating many of these disease states.

Accordingly, the present invention provides a method of treating acytokine-mediated disease which comprises administering an effectivecytokine-interfering amount of a compound of Formula (I) or apharmaceutically acceptable salt thereof.

Compounds of Formula (I) are capable of inhibiting inducibleproinflammatory proteins, such as COX-2, also referred to by many othernames such as prostaglandin endoperoxide synthase-2 (PGHS-2) and aretherefore of use in therapy. These proinflammatory lipid mediators ofthe cyclooxygenase (CO) pathway are produced by the inducible COX-2enzyme. Regulation, therefore of COX-2 which is responsible for thethese products derived from arachidonic acid, such as prostaglandinsaffect a wide variety of cells and tissues are important and criticalinflammatory mediators of a wide variety of disease states andconditions. Expression of COX-1 is not effected by compounds of Formula(I). This selective inhibition of COX-2 may alleviate or spareulcerogenic liability associated with inhibition of COX-1 therebyinhibiting prostoglandins essential for cytoprotective effects. Thusinhibition of these pro-inflammnatory mediators is of benefit incontrolling, reducing and alleviating many of these disease states. Mostnotably these inflammatory mediators, in particular prostaglandins, havebeen implicated in pain, such as in the sensitization of pain receptors,or edema. This aspect of pain management therefore includes treatment ofneuromuscular pain, headache, cancer pain, and arthritis pain. Compoundsof Formula (I) or a pharmaceutically acceptable salt thereof, are of usein the prophylaxis or therapy in a human, or other mammal, by inhibitionof the synthesis of the COX-2 enzyme.

Accordingly, the present invention provides a method of inhibiting thesynthesis of COX-2 which comprises administering an effective amount ofa compound of Formula (I) or a pharmaceutically acceptable salt thereof.The present invention also provides for a method of prophylaxistreatment in a human, or other mammal, by inhibition of the synthesis ofthe COX-2 enzyme.

A new member of the MAP kinase family, alternatively termed CSBP, p38,or RK, has been identified independently by several laboratoriesrecently. Activation of this novel protein kinase via dualphosphorylation has been observed in different cell systems uponstimulation by a wide spectrum of stimuli, such as physicochemicalstress and treatment with lipopolysaccharide or proinflammatorycytokines such as interleukin-1 and tumor necrosis factor. The cytokinebiosynthesis inhibitors, of the present invention, compounds of Formula(I), have been determined to be potent and selective inhibitors ofCSBP/p38/RK kinase activity. These inhibitors are of aid in determiningthe signaling pathways involvement in inflammatory responses. Inparticular, for the first time a definitive signal transduction pathwaycan be prescribed to the action of lipopolysaccharide in cytokineproduction in macrophages.

The cytokine inhibitors were subsequently tested in a number of animalmodels for anti-inflammatory activity. Model systems were chosen thatwere relatively insensitive to cyclooxygenase inhibitors in order toreveal the unique activities of cytokine suppressive agents. Theinhibitors exhibited significant activity in many such in vivo studies.Most notable are its effectiveness in the collagen-induced arthritismodel and inhibition of TNF production in the endotoxic shock model. Inthe latter study, the reduction in plasma level of TNF correlated withsurvival and protection from endotoxic shock related mortality. Also ofgreat importance are the compounds effectiveness in inhibiting boneresorption in a rat fetal long bone organ culture system. Griswold etal., (1988) Arthritis Rheum. 31:1406-1412; Badger, et al., (1989) Circ.Shock 27, 51-61; Votta et al., (1994) in vitro. Bone 15, 533-538; Lee etal., (1993). B Ann. N. Y. Acad. Sci. 696,149-170.

Another aspect of the present invention, therefore, is the treatment ofa CSBP/RK/p38 kinase mediated disease, in a mammal in need thereof,which comprises administering to said mammal an effective amount of acompound of Formula (I). Suitable diseases, include those mentionedherein for IL-1, IL-6, IL-8 and TNF and more specifically those diseasewhich are CSBP/RK/p38 kinase mediated diseases. These include, but arenot limited to rheumatoid arthritis, rheumatoid spondylitis,osteoarthritis, gouty arthritis and other arthritic conditions, sepsis,septic shock, endotoxic shock, gram negative sepsis, toxic shocksyndrome, asthma, adult respiratory distress syndrome, stroke,reperfusion injury, CNS injuries, such as neurotrauma and ischemia,including both open and closed head injuries), psoriasis, restenosis,such as occurs following coronary angioplasty, cerebral malaria, chronicpulmonary inflammatory disease, silicosis, pulmonary sarcososis, boneresorption diseases, osteoporosis, graft vs. host reaction, allograftrejections, Crohn's disease, ulcerative colitis or any otheranti-inflammatory bowel disease (IBD), or pyresis.

CNS injuries as defined herein include both open or penetrating headtrauma, such as by surgery, or a closed head trauma injury, such as byan injury to the head region. Also included within this definition isischemic stroke, particularly to the brain area.

Ischemic stroke may be defined as a focal neurologic disorder thatresults from insufficient blood supply to a particular brain area,usually as a consequence of an embolus, thrombi, or local atheromatousclosure of the blood vessel. The role of inflammatory cytokines in thisare has been emerging and the present invention provides a mean for thepotential treatment of these injuries. Relatively little treatment, foran acute injury such as these has been available.

TNF-α is a cytokine with proinflammatory actions, including endothelialleukocyte adhesion molecule expression. Leukocytes infiltrate intoischemic brain lesions and hence compounds which inhibit or decreaselevels of TNF would be useful for treatment of ischemic brain injury.See Liu et al., Stoke, Vol. 25, No. 7, pp 1481-88 (1994) whosedisclosure is incorporated herein by reference.

Models of closed head injuries and treatment with mixed 5-LO/CO agentsis discussed in Shohami et al., J. of Vaisc & Clinical Physiology andPharmacology, Vol. 3, No. 2, pp. 99-107 (1992) whose disclosure isincorporated herein by reference. Treatment which reduced edemaformation was found to improve functional outcome in those animalstreated.

Another aspect of the present invention is to use of a compound ofFormula (I) for the treatment of chronic inflammatory or proliferativeor angiogenic diseases which are caused by excessive, inappropriateangiogenesis. Compounds of Formula (I) may also be used topically in thetreatment or prophylaxis of disease states exacerbated by excessive orinappropriate angiogenesis.

Chronic diseases which have an inappropriate angiogenic component arevarious ocular neovasularizations, such as diabetic retinopathy andmacular degeneration.

Other chronic diseases which have an excessive or increasedproliferation of vasculature are tumor growth and metastasis,atherosclerosis, and certain arthritic conditions. Therefore cytokineinhibitors will be of utility in the blocking of the angiogeniccomponent of these disease states.

The term “excessive or increased proliferation of vasculatureinappropriate angiogenesis” as used herein includes, but is not limitedto, diseases which are characterized by hemangiomas and ocular diseases.

The term “inappropriate angiogenesis” as used herein includes, but isnot limited to, diseases which are characterized by vesicleproliferation with accompanying tissue proliferation, such as occurs incancer, metastasis, arthritis and atherosclerosis.

The murine airpouch granuloma model of chronic inflammation (Kimura etal., 1985, J. Pharmacobio-Dyn., 8:393-400; Colville-Nash et al.,1995, J.Pharm. and Exp. Ther., 274:1463-1472) whose disclosure is incorporatedherein by reference in its entirety, is characterized by inflammatorycell influx, fibrous tissue proliferation and intense angiogenesis. Itis representative of inflammatory angiogenesis and demonstrates that theangiogenic component can be pharmacologically modulated independently ofgranuloma growth and size. In addition, angiogenesis can be accuratelyquantitated by a vascular casting method. For additional information onscreening, etc., see Winkler et al., U.S. Ser. No. 60/013,138 nowPCT/US97/03626, filed Mar. 7, 1997, whose disclosure is incorporatedherein be reference.

In particular, compounds of Formula (I) or a pharmaceutically acceptablesalt thereof are of use in the prophylaxis or therapy of any diseasestate in a human, or other mammal, which is exacerbated by or caused byexcessive or unregulated IL-1, IL-8 or TNF production by such mammal'scell, such as, but not limited to, monocytes and/or macrophages.

Accordingly, in another aspect, this invention relates to a method ofinhibiting the production of IL-1in a mammal in need thereof whichcomprises administering to said mammal an effective amount of a compoundof Formula (I) or a pharmaceutically acceptable salt thereof.

There are many disease states in which excessive or unregulatedIL-1production is implicated in exacerbating and/or causing the disease.These include rheumatoid arthritis, osteoarthritis, stroke, endotoxemiaand/or toxic shocksyndrome, other acute or chronic inflammatory diseasestates such as the inflammatory reaction induced by endotoxin orinflammatory bowel disease, tuberculosis, atherosclerosis, muscledegeneration, multiple sclerosis, cachexia, bone resorption, psoriaticarthritis, Reiter's syndrome, rheumatoid arthritis, gout, traumaticarthritis, rubella arthritis and acute synovitis. Recent evidence alsolinks IL-1activity to diabetes, pancreatic β cells and Alzheimer'sdisease.

In a further aspect, this invention relates to a method of inhibitingthe production of TNF in a mammal in need thereof which comprisesadministering to said mammal an effective amount of a compound ofFormula (I) or a pharmaceutically acceptable salt thereof.

Excessive or unregulated TNF production has been implicated in mediatingor exacerbating a number of diseases including rheumatoid arthritis,rheumatoid spondylitis, osteoarthritis, gouty arthritis and otherarthritic conditions, sepsis, septic shock, endotoxic shock, gramnegative sepsis, toxic shock syndrome, adult respiratory distresssyndrome, stroke, cerebral malaria, chronic pulmonary inflammatorydisease, silicosis, pulmonary sarcoisosis, bone resorption diseases,such as osteoporosis, reperfusion injury, graft vs. host reaction,allograft rejections, fever and myalgias due to infection, such asinfluenza, cachexia secondary to infection or malignancy, cachexiasecondary to acquired immune deficiency syndrome (AIDS), AIDS, ARC (AIDSrelated complex), keloid formation, scar tissue formation, Crohn'sdisease, ulcerative colitis and pyresis.

Compounds of Formula (I) are also useful in the treatment of viralinfections, where such viruses are sensitive to upregulation by TNF orwill elicit TNF production in vivo. The viruses contemplated fortreatment herein are those that produce TNF as a result of infection, orthose which are sensitive to inhibition, such as by decreasedreplication, directly or indirectly, by the TNF inhibiting-compounds ofFormula (1). Such viruses include, but are not limited to HIV-1, HIV-2and HIV-3, Cytomegalovirus (CMV), Influenza, adenovirus and the Herpesgroup of viruses, such as but not limited to, Herpes Zoster and HerpesSimplex. Accordingly, in a further aspect, this invention relates to amethod of treating a mammal afflicted with a human immunodeficiencyvirus (HIV) which comprises administering to such mammal an effectiveTNF inhibiting amount of a compound of Formula (I) or a pharmaceuticallyacceptable salt thereof.

Compounds of Formula (I) may also be used in association with theveterinary treatment of mammals, other than in humans, in need ofinhibition of TNF production. TNF mediated diseases for treatment,therapeutically or prophylactically, in animals include disease statessuch as those noted above, but in particular viral infections. Examplesof such viruses include, but are not limited to, lentivirus infectionssuch as, equine infectious anaemia virus, caprine arthritis virus, visnavirus, or maedi virus or retrovirus infections, such as but not limitedto feline immunodeficiency virus (FIV), bovine immunodeficiency virus,or canine immunodeficiency virus or other retroviral infections.

The compounds of Formula (I) may also be used topically in the treatmentor prophylaxis of topical disease states mediated by or exacerbated byexcessive cytokine production, such as by IL-1or TNF respectively, suchas inflamed joints, eczema, psoriasis and other inflammatory skinconditions such as sunburn inflammatory eye conditions includingconjunctivitis; pyresis, pain and other conditions associated withinflammation.

Compounds of Formula (I) have also been shown to inhibit the productionof IL-8 (Interleukin-8, NAP). Accordingly, in a further aspect, thisinvention relates to a method of inhibiting the production of IL-8 in amammal in need thereof which comprises administering to said mammal aneffective amount of a compound of Formula (I) or a pharmaceuticallyacceptable salt thereof.

There are many disease states in which excessive or unregulated IL-8production is implicated in exacerbating and/or causing the disease.These diseases are characterized by massive neutrophil infiltration suchas, psoriasis, inflammatory bowel disease, asthma, cardiac and renalreperfusion injury, adult respiratory distress syndrome, thrombosis andglomerulonephritis. All of these diseases are associated with increasedIL-8 production which is responsible for the chemotaxis of neutrophilsinto the inflammatory site. In contrast to other inflammatory cytokines(IL-1, TNF, and IL-6), IL-8 has the unique property of promotingneutrophil chemotaxis and activation. Therefore, the inhibition ofIL-8production would lead to a direct reduction in the neutrophilinfiltration.

The compounds of Formula (I) are administered in an amount sufficient toinhibit cytokine, in particular IL-1, IL-6, IL-8 or TNF, production suchthat it is regulated down to normal levels, or in some case to subnormallevels, so as to ameliorate or prevent the disease state. Abnormnallevels of IL-1, IL-6, IL-8 or TNF, for instance in the context of thepresent invention, constitute: (i) levels of free (not cell bound) IL-1,IL-6, IL-8 or TNF greater than or equal to 1 picogram per ml; (ii) anycell associated IL-1, IL-6, IL-8 or TNF; or (iii) the presence of IL-1,IL-6, IL-8 or TNF mRNA above basal levels in cells or tissues in whichIL-1, IL-6, IL-8 or TNF, respectively, is produced.

The discovery that the compounds of Formula (I) are inhibitors ofcytokines, specifically IL-1, IL-6, IL-8 and TNF is based upon theeffects of the compounds of Formulas (I) on the production of the IL-1,IL-8 and TNF in in vitro assays which are described herein.

As used herein, the term “inhibiting the production of IL-1(IL-6, IL-8or TNF)” refers to:

a) a decrease of excessive in vivo levels of the cytokine (IL-1, IL-6,IL-8 or TNF) in a human to normal or sub-normal levels by inhibition ofthe in vivo release of the cytokine by all cells, including but notlimited to monocytes or macrophages;

b) a down regulation, at the genomic level, of excessive in vivo levelsof the cytokine (IL-1, IL-6, IL-8 or TNF) in a human to normal orsub-normal levels;

c) a down regulation, by inhibition of the direct synthesis of thecytokine (IL-1, IL-6, IL-8 or TNF) as a postranslational event; or

d) a down regulation, at the translational level, of excessive in vivolevels of the cytokine (IL-1, IL-6, IL-8 or TNF) in a human to normal orsubnormal levels.

As used herein, the term “TNF mediated disease or disease state” refersto any and all disease states in which TNF plays a role, either byproduction of TNF itself, or by TNF causing another monokine to bereleased, such as but not limited to IL-1, IL-6or IL-8. A disease statein which, for instance, IL-1is a major component, and whose productionor action, is exacerbated or secreted in response to TNF, wouldtherefore be considered a disease stated mediated by TNF.

As used herein, the term “cytokine” refers to any secreted polypeptidethat affects the functions of cells and is a molecule which modulatesinteractions between cells in the immune, inflammatory or hematopoieticresponse. A cytokine includes, but is not limited to, monokines andlymphokines, regardless of which cells produce them. For instance, amonokine is generally referred to as being produced and secreted by amononuclear cell, such as a macrophage and/or monocyte. Many other cellshowever also produce monokines, such as natural killer cells,fibroblasts, basophils, neutrophils, endothelial cells, brainastrocytes, bone marrow stromal cells, epideral keratinocytes andB-lymphocytes. Lymphokines are generally referred to as being producedby lymphocyte cells. Examples of cytokines include, but are not limitedto, Interleukin-1 (IL-1), Interleukin-6 (IL-6), Interleukin-8 (IL-8),Tumor Necrosis Factor-alpha (TNF-a) and Tumor Necrosis Factor beta(TNF-β).

As used herein, the term “cytokine interfering” or “cytokine suppressiveamount” refers to an effective amount of a compound of Formula (I) whichwill cause a decrease in the in vivo levels of the cytokine to normal orsub-normal levels, when given to a patient for the prophylaxis ortreatment of a disease state which is exacerbated by, or caused by,excessive or unregulated cytokine production.

As used herein, the cytokine referred to in the phrase “inhibition of acytokine, for use in the treatment of a HIV-infected human” is acytokine which is implicated in (a) the initiation and/or maintenance ofT cell activation and/or activated T cell-mediated HIV gene expressionand/or replication and/or (b) any cytokine-mediated disease associatedproblem such as cachexia or muscle degeneration.

As TNF-β (also known as lymphotoxin) has close structural homology withTNF-a (also known as cachectin) and since each induces similar biologicresponses and binds to the same cellular receptor, both TNF-a and TNF-βare inhibited by the compounds of the present invention and thus areherein referred to collectively as “TNF” unless specifically delineatedotherwise.

In order to use a compound of Formula (I) or a pharmaceuticallyacceptable salt thereof in therapy, it will normally be Formulated intoa pharmaceutical composition in accordance with standard pharmaceuticalpractice. This invention, therefore, also relates to a pharmaceuticalcomposition comprising an effective, non-toxic amount of a compound ofFormula (I) and a pharmaceutically acceptable carrier or diluent.

Compounds of Formula (I), pharmaceutically acceptable salts thereof andpharmaceutical compositions incorporating such may conveniently beadministered by any of the routes conventionally used for drugadministration, for instance, orally, topically, parenterally or byinhalation. The compounds of Formula (I) may be administered inconventional dosage forms prepared by combining a compound of Formula(I) with standard pharmaceutical carriers according to conventionalprocedures. The compounds of Formula (I) may also be administered inconventional dosages in combination with a known, second therapeuticallyactive compound. These procedures may involve mixing, granulating andcompressing or dissolving the ingredients as appropriate to the desiredpreparation. It will be appreciated that the form and character of thepharmaceutically acceptable character or diluent is dictated by theamount of active ingredient with which it is to be combined, the routeof administration and other well-known variables. The carrier(s) must be“acceptable” in the sense of being compatible with the other ingredientsof the Formulation and not deleterious to the recipient thereof.

The pharmaceutical carrier employed may be, for example, either a solidor liquid. Exemplary of solid carriers are lactose, terra alba, sucrose,talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acidand the like. Exemplary of liquid carriers are syrup, peanut oil, oliveoil, water and the like. Similarly, the carrier or diluent may includetime delay material well known to the art, such as glycerylmono-stearate or glyceryl distearate alone or with a wax.

A wide variety of pharmaceutical forms can be employed. Thus, if a solidcarrier is used, the preparation can be tableted, placed in a hardgelatin capsule in powder or pellet form or in the form of a troche orlozenge. The amount of solid carrier will vary widely but preferablywill be from about 25 mg. to about 1 g. When a liquid carrier is used,the preparation will be in the form of a syrup, emulsion, soft gelatincapsule, sterile injectable liquid such as an ampule or nonaqueousliquid suspension.

Compounds of Formula (I) may be administered topically, that is bynon-systemic administration. This includes the application of a compoundof Formula (I) externally to the epidermis or the buccal cavity and theinstillation of such a compound into the ear, eye and nose, such thatthe compound does not significantly enter the blood stream. In contrast,systemic administration refers to oral, intravenous, intraperitoneal andintramuscular administration.

Formulations suitable for topical administration include liquid orsemi-liquid preparations suitable for penetration through the skin tothe site of inflammation such as liniments, lotions, creams, ointmentsor pastes, and drops suitable for administration to the eye, ear ornose. The active ingredient may comprise, for topical administration,from 0.001% to 10% w/w, for instance from 1% to 2% by weight of theFormulation. It may however comprise as much as 10% w/w but preferablywill comprise less than 5% w/w, more preferably from 0.1% to 1% w/w ofthe Formulation.

Lotions according to the present invention include those suitable forapplication to the skin or eye. An eye lotion may comprise a sterileaqueous solution optionally containing a bactericide and may be preparedby methods similar to those for the preparation of drops. Lotions orliniments for application to the skin may also include an agent tohasten drying and to cool the skin, such as an alcohol or acetone,and/or a moisturizer such as glycerol or an oil such as castor oil orarachis oil.

Creams, ointments or pastes according to the present invention aresemi-solid formulations of the active ingredient for externalapplication. They may be made by mixing the active ingredient infinely-divided or powdered form, alone or in solution or suspension inan aqueous or non-aqueous fluid, with the aid of suitable machinery,with a greasy or non-greasy base. The base may comprise hydrocarbonssuch as hard, soft or liquid paraffin, glycerol, beeswax, a metallicsoap; a mucilage; an oil of natural origin such as almond, corn,arachis, castor or olive oil; wool fat or its derivatives or a fattyacid such as stearic or oleic acid together with an alcohol such aspropylene glycol or a macrogel. The formulation may incorporate anysuitable surface active agent such as an anionic, cationic or non-ionicsurfactant such as a sorbitan ester or a polyoxyethylene derivativethereof. Suspending agents such as natural gums, cellulose derivativesor inorganic materials such as silicaceous silicas, and otheringredients such as lanolin, may also be included.

Drops according to the present invention may comprise sterile aqueous oroily solutions or suspensions and may be prepared by dissolving theactive ingredient in a suitable aqueous solution of a bactericidaland/or fungicidal agent and/or any other suitable preservative, andpreferably including a surface active agent. The resulting solution maythen be clarified by filtration, transferred to a suitable containerwhich is then sealed and sterilized by autoclaving or maintaining at98-100° C. for half an hour. Alternatively, the solution may besterilized by filtration and transferred to the container by an aseptictechnique. Examples of bactericidal and fungicidal agents suitable forinclusion in the drops are phenylmercuric nitrate or acetate (0.002%),benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%).Suitable solvents for the preparation of an oily solution includeglycerol, diluted alcohol and propylene glycol.

Compounds of formula (I) may be administered parenterally, that is byintravenous, intramuscular, subcutaneous intranasal, intrarectal,intravaginal or intraperitoneal administration. The subcutaneous andintramuscular forms of parental administration are generally preferred.Appropriate dosage forms for such administration may be prepared byconventional techniques. Compounds of Formula (I) may also beadministered by inhalation, that is by intranasal and oral inhalationadministration. Appropriate dosage forms for such administration, suchas an aerosol formulation or a metered dose inhaler, may be prepared byconventional techniques.

For all methods of use disclosed herein for the compounds of Formula(I), the daily oral dosage regimen will preferably be from about 0.01 toabout 80 mg/kg of total body weight, preferably from about 0.1 to 30mg/kg, more preferably from about 0.2 mg to 15 mg. The daily parenteraldosage regimen about 0.01 to about 80 mg/kg of total body weight,preferably from about 0.1 to about 30 mg/kg, and more preferably fromabout 0.2 mg to 15 mg/kg. The daily topical dosage regimen willpreferably be from 0.1 mg to 150 mg, administered one to four,preferably two or three times daily. The daily inhalation dosage regimenwill preferably be from about 0.01 mg/kg to about 1 mg/kg per day. Itwill also be recognized by one of skill in the art that the optimalquantity and spacing of individual dosages of a compound of Formula (I)or a pharmaceutically acceptable salt thereof will be determined by thenature and extent of the condition being treated, the form, route andsite of administration, and the particular patient being treated, andthat such optimums can be determined by conventional techniques. It willalso be appreciated by one of skill in the art that the optimal courseof treatment, i.e., the number of doses of a compound of Formula (I) ora pharmaceutically acceptable salt thereof given per day for a definednumber of days, can be ascertained by those skilled in the art usingconventional course of treatment determination tests.

The novel compounds of Formula (I) may also be used in association withthe veterinary treatment of mammals, other than humans, in need ofinhibition of cytokine inhibition or production. In particular, cytokinemediated diseases for treatment, therapeutically or prophylactically, inanimals include disease states such as those noted herein in the Methodsof Treatment section, but in particular viral infections. Examples ofsuch viruses include, but are not limited to, lentivirus infections suchas, equine infectious anaemia virus, caprine arthritis virus, visnavirus, or maedi virus or retrovirus infections, such as but not limitedto feline immunodeficiency virus (FIV), bovine immunodeficiency virus,or canine immunodeficiency virus or other retroviral infections.

The invention will now be described by reference to the followingbiological examples which are merely illustrative and are not to beconstrued as a limitation of the scope of the present invention.

Biological Examples

The cytokine-inhibiting effects of compounds of the present inventionwere determined by the following in vitro assays:

Interleukin-1 (IL-1)

Human peripheral blood monocytes are isolated and purified from eitherfresh blood preparations from volunteer donors, or from blood bank buffycoats, according to the procedure of Colotta et al, J Immunol, 132, 936(1984). These monocytes (1×10⁶) are plated in 24-well plates at aconcentration of 1-2 million/ml per well. The cells are allowed toadhere for 2 hours, after which time non-adherent cells are removed bygentle washing. Test compounds are then added to the cells for 1 hbefore the addition of lipopolysaccharide (50 ng/ml), and the culturesare incubated at 37° C. for an additional 24 h. At the end of thisperiod, culture supernatants are removed and clarified of cells and alldebris. Culture supernatants are then immediately assayed forIL-1biological activity, either by the method of Simon et al., J.Immunol. Methods, 84, 85, (1985) (based on ability of IL-1to stimulate aInterleukin 2 producing cell line (EL-4) to secrete IL-2, in concertwith A23187 ionophore) or the method of Lee et al., J. ImmunoTherapy, 6(1), 1-12 (1990) (ELISA assay).

Tumour Necrosis Factor (TNF)

Human peripheral blood monocytes are isolated and purified from eitherblood bank buffy coats or platelet pheresis residues, according to theprocedure of Colotta, R. et al., J Immunol, 132(2), 936 (1984). Themonocytes are plated at a density of 1×10⁶ cells/ml medium/well in24-well multi-dishes. The cells are allowed to adhere for 1 hour afterwhich time the supernatant is aspirated and fresh medium (1 ml,RPMI-1640, Whitaker Biomedical Products, Whitaker, Calif.) containing 1%fetal calf serum plus penicillin and streptomycin (10 units/ml) added.The cells are incubated for 45 minutes in the presence or absence of atest compound at 1 nM-10 mM dose ranges (compounds are solubilized indimethyl sulfoxide/ethanol, such that the final solvent concentration inthe culture medium is 0.5% dimethyl sulfoxide/0.5% ethanol). Bacteriallipopolysaccharide (E. coli 055:B5 [LPS] from Sigma Chemicals Co.) isthen added (100 ng/ml in 10 ml phosphate buffered saline) and culturesincubated for 16-18 hours at 37° C. in a 5% CO₂ incubator. At the end ofthe incubation period, culture supernatants are removed from the cells,centrifuged at 3000 rpm to remove cell debris. The supernatant is thenassayed for TNF activity using either a radio-immuno or an ELISA assay,as described in WO 92/10190 and by Becker et al., J Immunol, 1991, 147,4307.

IL-1and TNF inhibitory activity does not seem to correlate with theproperty of the compounds of Formula (I) in mediating arachidonic acidmetabolism inhibition. Further the ability to inhibit production ofprostagiandin and/or leukotriene synthesis, by nonsteroidalanti-inflammatory drugs with potent cyclooxygenase and/or lipoxygenaseinhibitory activity does not mean that the compound will necessarilyalso inhibit TNF or IL-1production, at nontoxic doses.

In Vivo TNF Assay

While the above indicated assay in an in vitro assay, the compounds ofFormula (I) may also be tested in an in vivo system such as describedin:

(1) “Differentiation In Vivo of Classical Non-Steroidal AntiintlammatoryDrugs from Cytokine Suppressive Antiinflammatory Drugs and OtherPharmacological Classes Using Mouse Tumour Necrosis Factor AlphaProduction”, Griswold et al., Drugs Under Exp. and Clinical Res.,XIX(6),243-248 (1993); or in

(2) Boehm, et al., 1-substituted 4-aryl-5-pyridinylimidazoles—a newclass of cytokine suppressive drugs with low 5-lipoxygenase andcyclooxygenase inhibitory potency. Journal Of Medicinal Chemistry 39,3929-3937 (1996) whose disclosures are incorporated by reference hereinin their entirety.

Interleukin-8 (IL-8)

Primary human umbilical cord endothelial cells (HUVEC) (Cell Systems,Kirland, Wash.) are maintained in culture medium supplemented with 15%fetal bovine serum and 1% CS-HBGF consisting of aFGF and heparin. Thecells are then diluted 20-fold before being plated (250 μl) intogelating coated 96-well plates. Prior to use, culture medium arereplaced with fresh medium (200 μl). Buffer or test compound (25 μl, atconcentrations between 1 and 10 μM) is then added to each well inquadruplicate wells and the plates incubated for 6 h in a humidifiedincubator at 37° C. in an atmosphere of 5% CO₂. At the end of theincubation period, supernatant is removed and assayed for IL-8concentration using an IL-8 ELISA kit obtained from R&D Systems(Minneapolis, Minn.). All data is presented as mean value (ng/ml) ofmultiple samples based on the standard curve. IC₅₀'s where appropriateare generated by non-linear regression analysis.

Cytokine Specific Binding Protein Assay

A radiocompetitive binding assay was developed to provide a highlyreproducible primary screen for structure-activity studies. This assayprovides many advantages over the conventional bioassays which utilizefreshly isolated human monocytes as a source of cytokines and ELISAassays to quantify them. Besides being a much more facile assay, thebinding assay has been extensively validated to highly correlate withthe results of the bioassay. A specific and reproducible cytokineinhibitor binding assay was developed using soluble cystosolic fractionfrom THP.1 cells and a radiolabeled compound. Patent Application U.S.Ser. No. 08/123175 Lee et al., filed September 1993, U.S.S.N.; Lee etal., PCT 94/10529 filed Sep. 16, 1994 and Lee et al., Nature 300, n(72),739-746 (December 1994) whose disclosures are incorporated by referenceherein in its entirety describes the above noted method for screeningdrugs to identify compounds which interact with and bind to the cytokinespecific binding protein (hereinafter CSBP). However, for purposesherein the binding protein may be in isolated form in solution, or inimmobilized form, or may be genetically engineered to be expressed onthe surface of recombinant host cells such as in phage display system oras fusion proteins. Alternatively, whole cells or cytosolic fractionscomprising the CSBP may be employed in the screening protocol.Regardless of the form of the binding protein, a plurality of compoundsare contacted with the binding protein under conditions sufficient toform a compound/binding protein complex and compound capable of forming,enhancing or interfering with said complexes are detected.

Representative compounds of Formula (I), Examples 1 to 3 have alldemonstrated positive inhibitory activity in this binding assay.

CSBP Kinase Assay

This assay measures the CSBP-catalyzed transfer of ³²P from [a-³²P]ATPto threonine residue in an epidermal growth factor receptor(EGFR)-derived peptide (T669) with the following sequence:KRELVEPLTPSGEAPNQALLR (residues 661-681). (See Gallagher et al.,“Regulation of Stress Induced Cytokine Production by PyridinylImidazoles: Inhibition of CSPB Kinase”, BioOrganic & MedicinalChemistry, to be published 1996).

Kinase reactions (total volume 30 ul) contain: 25 mM Hepes buffer, pH7.5; 10 mM MgCl₂; 170 uM ATP⁽¹⁾; 10 uM Na ortho vanadate; 0.4 mM T669peptide; and 20-80 ng of yeast-expressed purified CSBP2 (see Lee et al.,Nature 300, n(72), 739-746 (Dec. 1994)). Compounds (5 ul from [6X]stock⁽²⁾) are pre-incubated with the enzyme and peptide for 20 min onice prior to starting the reactions with 32P/MgATP. Reactions areincubated at 30° C. for 10 min and stopped by adding 10 ul of 0.3 Mphosphoric acid. 32P-labeled peptide is separated on phosphocellulose(Wattman, p81) filters by spotting 30 ul reaction mixture. Filters arewashed 3 times with 75 mM phosphoric acid followed by 2 washes with H₂O,and counted for 32P.

(1) The Km of CSBP for ATP was determined to be 170 uM. Therefore,compounds screened at the Km value of ATP.

(2) Compounds are usually dissolved in DMSO and are diluted in 25 mMHepes buffer to get final concentration of DMSO of 0.17%.

Prostaglandin Endoperoxide Synthase-2 (PGHS-2) Assay

The following assay describes a method for determining the inhibitoryeffects of compounds of Formula (I) on human PGHS-2 protein expressionin LPS stimulated human monocytes. The assay shown below is demonstratedwith compounds other than that of Formula (I) herein:

Method: Human peripheral blood monocytes were isolated from buffy coatsby centrifugation through Ficoll and Percoll gradients. Cells wereseeded at 2×10⁶/well in 24 well plates and allowed to adhere for 1 hourin RPMI supplemented with 1% human AB serum, 20 mM L-glutamine,Penicillin-Streptomycin and 10 mM HEPES. Compounds were added at variousconcentrations and incubated at 37° C. for 10 minutes. LPS was added at50 ng/well (to induce enzyme expression) and incubated overnight at 37°C. The supernatant was removed and cells washed once in cold PBS. Thecells were lysed in 100 ml of cold lysis buffer(50 mM Tris/HCl pH 7.5,150 mM NaCl, 1% NP40, 0.5% sodium deoxycholate, 0.1% SDS, 300 ug/mlDNAse, 0.1% TRITON X-100, 1 mM PMSF, 1 mM leupeptin, 1 mM pepstatin).The lysate was centrifuged (10,000×g for 10 min. at 4° C.) to removedebris and the soluble fraction was subjected to SDS PAGE. analysis (12%gel). Protein separated on the gel were transferred onto nitrocellulosemembrane by electrophoretic means for 2 hours at 60 volts. The membranewas pretreated for one hour in PBS/0.1% Tween 20 with 5% non-fat drymilk. After washing 3 times in PBS/Tween buffer, the membrane wasincubated with a 1:2000 dilution of a monospecific antiserum to PGHS-2or a 1:1000 dilution of an antiserum to PGHs-1 in PBS/Tween with 1% BSAfor one hour with continuous shaking. The membrane was washed 3× inPBS/Tween and then incubated with a 1:3000 dilution of horseradishperoxidase conjugated donkey antiserum to rabbit Ig (Amersham) inPBS/Tween with 1% BSA for one hour with continuous shaking. The membranewas then washed 3× in PBS/Tween and the ECL immunodetection system(Amersham) was used to detect the level of expression of prostaglandinendoperoxide synthases-2.

Results: The following compounds were tested and found to be active inthis assay (i.e., inhibited LPS induced PGHS-2 protein expression inrank order potency similar to that for inhibiting cytokine production asnoted in assays indicated):6-(4-Fluoro-phenyl)-2,3-dihydro-5-(4-pyridinyl)imidazo[2,1-b]thiazole;and Dexamethasone.

Several compounds were tested and found to be inactive (up to 10 uM):2-(4-Methylsulfinylphenyl)-3-(4-pyridyl)-6,7-dihydro-(5H)-pyrrolo[1,2-a]imidazole;rolipram; phenidone and NDGA. None of these compounds tested were foundto inhibit PGHS-1 or cPLA₂ protein levels in similar experiments.

TNF-α in Traumatic Brain Injury Assay

The present assay provides for examination of the expression of tumornecrosis factor mnRNA in specific brain regions which followexperimentally induced lateral fluid-percussion traumatic brain injury(TBI) in rats. Adult Sprague-Dawley rats (n=42) are anesthetized withsodium pentobarbital (60 mg/kg, i.p.) and subjected to lateralfluid-percussion brain injury of moderate severity (2.4 atm.) centeredover the left temporaparietal cortex (n=18), or “sham” treatment(anesthesia and surgery without injury, n=18). Animals are sacrificed bydecapitation at 1, 6 and 24 hr. post injury, brains removed, and tissuesamples of left (injured) parietal cortex (LC), corresponding area inthe contralateral right cortex (RC), cortex adjacent to injured parietalcortex (LA), corresponding adjacent area in the right cortex (RA), lefthippocampus (LH) and right hippocampus (RH) are prepared. Total RNA isisolated and Northern blot hybridization is performed and quantitatedrelative to an TNF-a positive control RNA (macrophage=100%). A markedincrease of TNF-α mRNA expression is observed in LH (104±17% of positivecontrol, p<0.05 compared with sham), LC (105±21%, p<0.05) and LA (69±8%,p<0.01) in the traumatized hemisphere 1 hr. following injury. Anincreased TNF-α mRNA expression is also observed in LH (46±8%, p<0.05),LC (30±3%, p<0.01) and LA (32±3%, p<0.01) at 6 hr. which resolves by 24hr. following injury. In the contralateral hemisphere, expression ofTNF-α mRNA is increased in RH (46±2%, p<0.01), RC (4±3%) and RA (22±8%)at 1 hr. and in RH (28±11%), RC (7±5%) and RA (26±6%, p<0.05) at 6 hr.but not at 24 hr. following injury. In sham (surgery without injury) ornaive animals, no consistent changes in expression of TNF-α mRNA isobserved in any of the 6 brain areas in either hemisphere at any times.These results indicate that following parasagittal fluid-percussionbrain injury, the temporal expression of TNF-α mRNA is altered inspecific brain regions, including those of the nontraumatizedhemisphere. Since TNF-α is able to induce nerve growth factor (NGF) andstimulate the release of other cytokines from activated astrocytes, thispost-traumatic alteration in gene expression of TNF-α plays an importantrole in both the acute and regenerative response to CNS trauma.

CNS Injury Model for IL-β mRNA

This assay characterizes the regional expression of interleukin-1β(IL-1β) mRNA in specific brain regions following experimental lateralfluid-percussion traumatic brain injury (TBI) in rats. AdultSprague-Dawley rats (n=42) are anesthetized with sodium pentobarbital(60 mg/kg, i.p.) and subjected to lateral fluid-percussion brain injuryof moderate severity (2.4 atm.) centered over the left temporaparietalcortex (n=18), or “sham” treatment (anesthesia and surgery withoutinjury). Animals are sacrificed at 1, 6 and 24 hr. post injury, brainsremoved, and tissue samples of left (injured) parietal cortex (LC),corresponding area in the contralateral right cortex (RC), cortexadjacent to injured parietal cortex (LA), corresponding adjacent area inthe right cortex (RA), left hippocampus (LH) and right hippocampus (RH)were prepared. Total RNA is isolated and Northern blot hybridization isperformed and the quantity of brain tissue IL-1β mRNA is presented aspercent relative radioactivity of IL-1β positive macrophage RNA which isloaded on same gel. At 1 hr. following brain injury, a marked andsignificant increase in expression of IL-1β mRNA is observed in LC(20.0±0.7% of positive control, n=6, p<0.05compared with sham animal),LH 24.5±0.9%, p<0.05) and LA 21.5±3.1%, p<0.05) in the injuredhemisphere, which remained elevated up to 6 hr. post injury in the LC(4.0.±0.4%, n=6, p<0.05) and LH (5.0±1.3%, p<0.05). In sham or naiveanimals, no expression of IL-1β mRNA is observed in any of therespective brain areas. These results indicate that following TBI, thetemporal expression of IL-1β mRNA is regionally stimulated in specificbrain regions. These regional changes in cytokines, such as. IL-1β playa role in the post-traumatic pathologic or regenerative sequelae ofbrain injury.

SYNTHETIC EXAMPLES

The invention will now be described by reference to the followingexamples which are merely illustrative and are not to be construed as alimitation of the scope of the present invention. All temperatures aregiven in degrees centigrade, all solvents are highest available purityand all reactions run under anhydrous conditions in an argon atmosphereunless otherwise indicated.

In the Examples, all temperatures are in degrees Centigrade (° C.). Massspectra were performed upon a VG Zab mass spectrometer using fast atombombardment, unless otherwise indicated. ¹H-NMR (hereinafter “NMR”)spectra were recorded at 250 MHz using a Bruker AM 250 or Am 400spectrometer. Multiplicities indicated are: s=singlet, d=doublet,t=triplet, q=quartet, m=multiplet and br indicates a broad signal. Sat.indicates a saturated solution, eq indicates the proportion of a molarequivalent of reagent relative to the principal reactant. FlashChromatography is run over a Merck Silica gel 60 (230-400 mesh).

Example 1 4(5)-(4-Fluorophenyl)-5(4)-(4-pyridyl)imidazole

Pyridine-4-carboxaldehyde (321 mg, 3.0 mmol), and THF (3 mL) were cooledto −50° and lithium bis(trimethylsilyl)amide (LiBSA) (1 M in THF) (3 mL,3.0 mmol) was added dropwise (T<−40°), stirred for 45 min, and warmed to−30° for 5 min to afford Solution A.

THF (3 mL), and 4-Fluorophenyl(tosyl)methyl isocyanide (8) (see nextexperiment) (867 mg, 3.0 mmol) were cooled to −50° and LiBSA (1M in THF)(3 mL, 3.0 mmol) was added dropwise at −50°, stirred 30 min to affordSolution B.

Solution A was cooled to −60° and solution B was added dropwise. Theresulting solution was stirred at −70° for 30 min, warmed to 23° over 4h, stirred at 23° for 16 h, poured into 5% aq NA₂CO₃ (25 mL) andextracted with EtOAc (4×25 mL), dried (Na₂SO₄) concentrated and flashchromatographed (0-8% MeOH in CH₂Cl₂) to afford (28) 251 mg (35%). Theproduct was crystallized from acetone/hexane: ¹H NMR 8.42 (m,2), 7.72(s,1), 7.40 (m,4), 7.12 (m,2): MS (ES+) m/z=240 (MH⁺): mp 245-246 (dec).Anal. (C₁₄H₁₀FN₃. 1/10 H₂O) C, H, N.

4-Fluorophenyl(tosyl)methyl isocyanide

Toluenesulfinic acid sodium salt (150 g, 0.84 mol), H₂O (500 mL), andt-butylmethyl ether (TBME) (250 mL) were vigorously stirred, and concdHCl (75 mL) was added dropwise. The resulting two phases were separatedand the aqueous phase was extracted with TBME (100 mL). The TBME phaseswere dried (Na₂SO₄) and concentrated to near dryness and the white solidwas combined with hexane (350 mL) and filtered and dried in vacuo toafford 96 g of toluenesulfinic acid.

The free acid (92.3 g, 0.62 mol), p-fluorobenzaldehyde (92.3 g, 0.744mol), formamide (73.9 mL) and camphorsulfonic acid (14.4 g, 0.062 mol)were combined, vigorously stirred and heated to 65° for 16 h. Theresulting white mass was cooled to 23°, triturated with CH₃OH (150 mL)and hexane (350 mL), filtered and dried in vacuo to afford 88.35 g (46%)4-fluorophenyl tosylmethylformamide as a white solid:¹H NMR 8.06 (s,1H), 7.69 (d, J=8 Hz, 2H), 7.43 (m, 2H), 1.32 (d, J=8 Hz, 2H), 7.08 (m,2H), 6.29 (s, 1H), 2.43 (s, 3H).

A solution of the fornamide obtained above (20.2 g, 65.7 mmol), andanhydrous DME (330 mL) was cooled to −10° and POCl₃ (18.4 mL, 197 mmol)was added dropwise. Triethylamine (45.8 mL, 329 mmol) in DME (30 mL) wasadded dropwise (T<−5°) and the reaction was stirred at −5° for 2 h, thenpoured into H₂O (600 mL)and extracted with EtOAc (3×150 mL). Theextracts were washed with satd aq NaHCO₃, dried (Na₂SO₄) andconcentrated. The colorless oil was triturated with hexane to afford asolid. Filtration and drying afforded 16.2 g (85%) of4-fluorophenyl(tosyl)methyl isocanide as a white solid. ¹H NMR 7.62 (d,J=8 Hz. 2H), 7.34 (m, 4H), 7.10 (m, 2H), 5.59 (s, 1H), 2.48 (s, 3H).

Example 2 4-(4-Fluorophenvl)-5-(2-methoxy-pyrimidin-4-yl)imidazole

Prepared by the method of example 1 except using2-methoxypyrimidine-2-carboxaldehyde isocyanide to afford the titlecompound as a light brown powder. MS ES+m/z=287 (MH+).

Example 3 4-(4-Fluorophenyl)-5-(2-methylthio-pyrimidin-4-yl)imidazole

Prepared by the method of example 1 except using2-methoxypyrimidine-2-carboxaldehyde isocyanide to afford the titlecompound as a light brown powder. MS ES+m/z=287 (MH+).

All publications, including but not limited to patents and patentapplications, cited in this specification are herein incorporated byreference as if each individual publication were specifically andindividually indicated to be incorporated by reference herein as thoughfully set forth.

The above description fully discloses the invention including preferredembodiments thereof. Modifications and improvements of the embodimentsspecifically disclosed herein are within the scope of the followingclaims. Without further elaboration, it is believed that one skilled inthe art can, using the preceding description, utilize the presentinvention to its fullest extent. Therefore the Examples herein are to beconstrued as merely illustrative and not a limitation of the scope ofthe present invention in any way. The embodiments of the invention inwhich an exclusive property or privilege is claimed are defined asfollows.

What is claimed is:
 1. A compound of the formula:

wherein: R₁ is 4-pyridyl, pyrimidinyl, 4-pyridazinyl,1,2,4-triazin-5-yl, quinolyl, isoquinolinyl, quinazolin-4-yl,1-imidazolyl or 1-benzimidazolyl ring, which ring is optionallysubstituted independently one to three times with Y, NHR_(a), optionallysubstituted C₁₋₄ alkyl, halogen, hydroxyl, optionally substituted C₁₋₄alkoxy, optionally substituted C₁₋₄ alkylthio, C₁₋₄ alkylsulfinyl,CH₂OR₁₂, amino, mono and di-C₁₋₆ alkyl substituted amino,N(R₁₀)C(O)R_(b), or an N-heterocyclyl ring which ring has from 5 to 7members and optionally contains an additional heteroatom selected fromoxygen, sulfur; Y is X₁—R_(a); X₁ is oxygen or sulfur; R₄ is phenyl,naphth-1-yl or naphth-2-yl, which is optionally substituted by one ortwo substituents, each of which is independently selected, and which,for a 4-phenyl, 4-naphth-1-yl, 5-naphth-2-yl or 6-naphth-2-ylsubstituent, is halogen, cyano, nitro, C(Z)NR₇R₁₇, C(Z)OR₁₆,(CR₁₀R₂₀)_(v)COR₁₂, SR₅, SOR₅, OR₁₂, halo-substituted-C₁₋₄ alkyl, C₁₋₄alkyl, ZC(Z)R₁₂, NR₁₀C(Z)R₁₆, or (CR₁₀R₂₀)_(v)NR₁₀R₂₀ and which, forother positions of substitution, is halogen, cyano, C(Z)NR₁₃R₁₄,C(Z)OR₃, (CR₁₀R₂₀)_(m″)COR₃, S(O)_(m)R₃, OR₃, halo-substituted-C₁₋₄alkyl, C₁₋₄ alkyl, (CR₁₀R₂₀)_(m″)NR₁₀C(Z)R₃, NR₁₀S(O)_(m′)R₈,NR₁₀S(O)_(m′)NR₇R₁₇, ZC(Z)R₃ or (CR₁₀R₂₀)_(m″)NR₁₃R₁₄; v is 0, or aninteger having a value of 1 or 2; m is 0, or the integer 1 or 2; m′ isan integer having a value of 1 or 2, m″ is 0, or an integer having avalue of 1 to 5; n is an integer having a value of 1 to 10; Z is oxygenor sulfur; R_(a) is aryl, arylC₁₋₆alkyl, heterocyclic, heterocyclylC₁₋₆alkyl, heteroaryl, or heteroaryl C₁₋₆alkyl, wherein each of thesemoieties may be optionally substituted; R_(b) is hydrogen, C₁₋₆alkyl,C₃₋₇ cycloalkyl, aryl, arylC₁₋₄ alkyl, heteroaryl, heteroarylC₁₋₄alkyl,heterocyclyl, or heterocyclylC₁₋₄ alkyl; R₃ is heterocyclyl,heterocyclylC₁₋₁₀ alkyl or R₈; R₅ is hydrogen, C₁₋₄ alkyl, C₂₋₄ alkenyl,C₂₋₄ alkynyl or NR₇R₁₇, excluding the moieties —SR₅being —SNR₇R₁₇ and—SOR₅being —SOH; R₇ and R₁₇ is each independently selected from hydrogenor C₁₋₄ alkyl or R₇ and R₁₇ together with the nitrogen to which they areattached form a heterocyclic ring of 5 to 7 members which ringoptionally contains an additional heteroatom selected from oxygen,sulfur or NR₁₅; R₈ is C₁₋₁₀ alkyl, halo-substituted C₁₋₁₀ alkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, C₃₋₇ cycloalkyl, C₅₋₇ cycloalkenyl, aryl,arylC₁₋₁₀ alkyl, heteroaryl, heteroarylC₁₋₁₀ alkyl, (CR₁₀R₂₀)_(n)OR₁₁,(CR₁₀R₂₀)_(n)S(O)_(m)R₁₈, or (CR₁₀R₂₀)_(n)NHS(O)₂R₁₈,(CR₁₀R₂₀)_(n)NR₁₃R₁₄; wherein the aryl, arylalkyl, heteroaryl,heteroaryl alkyl may be optionally substituted; R₉ is hydrogen, C(Z)R₁₁or optionally substituted C₁₋₁₀ alkyl, S(O)₂R₁₈, optionally substitutedaryl or optionally substituted aryl-C₁₋₄ alkyl; R₁₀ and R₂₀ is eachindependently selected from hydrogen or C₁₋₄ alkyl; R₁₁ is hydrogen,C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, heterocyclyl, heterocyclyl C₁₋₁₀alkyl,aryl, arylC₁₋₁₀ alkyl, heteroaryl or heteroarylC₁₋₁₀ alkyl; R₁₂ ishydrogen or R₁₆; R₁₃ and R₁₄ is each independently selected fromhydrogen or optionally substituted C₁₋₄ alkyl, optionally substitutedaryl or optionally substituted aryl-C₁₋₄ alkyl, or together with thenitrogen to which they are attached form a heterocyclic ring of 5 to 7members which ring optionally contains an additional heteroatom selectedfrom oxygen, sulfur or NR₉; R₁₅ is R₁₀ or C(Z)—C₁₋₄ alkyl; R₁₆ is C₁₋₄alkyl, halo-substituted-C₁₋₄ alkyl, or C₃₋₇ cycloalkyl; R₁₈ is C₁₋₁₀alkyl, C₃₋₇ cycloalkyl, heterocyclyl, aryl, arylalkyl, heterocyclyl,heterocyclyl-C₁₋₁₀alkyl, heteroaryl or heteroarylalkyl; or apharmaceutically acceptable salt thereof.
 2. The compound according toclaim 1 wherein R₁ is an optionally substituted 4-pyridyl or4-pyrimindyl.
 3. The compound according to claim 2 wherein the optionalsubstituent is Y or NHR_(a).
 4. The compound according to claim 3wherein X₁ is oxygen and R_(a) is optionally substituted aryl, arylalkylor alkyl.
 5. The compound according to claim 2 wherein R₄ is anoptionally substituted phenyl.
 6. The compound according to claim 5wherein the phenyl is substituted one or more times independently byhalogen, SR₅, S(O)R₅, OR₁₂, halo-substituted-C₁₋₄ alkyl, or C₁₋₄ alkyl.7. The compound according to claim 1 which is:4-(4-Fluorophenyl)-5-(4-pyridyl)imidazole;4-(4-Fluorophenyl)-5-(2-methoxy-pyrimidin-4-yl)imidazole;4-(4-Fluorophenyl)-5-(2-methylthio-pyrimidin-4-yl)imidazole; or apharmaceutically acceptable salt thereof.
 8. A pharmaceuticalcomposition comprising a compound according to claim 1 and apharmaceutically acceptable carrier or diluent.
 9. A method of treatinga CSBP/RK/p38 kinase mediated disease, in a mammal in need thereof,which comprises administering to said mammal an effective amount of acompound of Formula (I) according to claim
 1. 10. The method accordingto claim 9 wherein the CSBP/RK/p38 kinase mediated disease is selectedselected from psoriatic arthritis, Reiter's syndrome, rheumatoidarthritis, gout, traumatic arthritis, rubella arthritis and acutesynovitis, rheumatoid spondylitis, osteoarthritis, gouty arthritis andother arthritic condition, sepsis, septic shock, endotoxic shock, gramnegative sepsis, toxic shock syndrome, Alzheimer's disease, stroke,neurotrauma, asthma, adult respiratory distress syndrome, cerebralmalaria, chronic pulmonary inflammatory disease, silicosis, pulmonarysarcososis, bone resorption disease, osteoporosis, restenosis, cardiacand renal reperfusion injury, thrombosis, glomerularonephritis,diabetes, graft vs. host reaction, allograft rejection, inflammatorybowel disease, Crohn's disease, ulcerative colitis, multiple sclerosis,muscle degeneration, eczema, contact dermatitis, psoriasis, sunburn, orconjunctivitis.
 11. The method according to claim 10 wherein the diseaseis asthma, osteoporosis, or arthritis.
 12. A method of treatinginflammation in a mammal in need thereof, which comprises administeringto said mammal an effective amount of a compound of Formula (I)according to claim
 1. 13. A method of treating osteoporosis in a mammalin need thereof, which comprises administering to said mammal aneffective amount of a compound of Formula (I) according to claim
 1. 14.A method of treating a chronic disease in a mammal in need thereof,which disease is characterized by excessive, undesired or inappropriateangiogenesis, with an effective amount of a compound according toclaim
 1. 15. The method according to claim 14 wherein the disease isdiabetic retinopathy and other ocular neovascularizations.
 16. Themethod according to claim 14 wherein the disease is tumor growth andmetastosis.
 17. The method according to claim 14 wherein the disease isatherosclerosis.
 18. The method according to claim 1 wherein the diseaseis arthritis.